Physostigmine derivatives



United States Patent i PHYSOSTIGMINE DERIVATIVES Bernard Rudner,Pittsburgh, Pa., assignor to W. R. Grace & Co., New York, N.Y., acorporation of Connecticut No Drawing. Application September 26, 1958Serial No. 763,429

3 Claims. (Cl. 260-319) This invention relates to quaternary nitrogenoussalts. In one specific aspect, it relates to quaternized derivatives ofsubstituted indoles related to physostigmine.

Physostigmine, also called eserine, and certain ofits derivatives arewell known compounds useful in the treatment of glaucoma and otherconditions. I have discovered a heretofore unavailable class ofpharmaceutically useful eserine derivatives.

It is therefore an object of the present invention to provide a newgeneric class of hypotensive hydrazinium compounds. The compounds of myinvention are conveniently prepared by the action of chloramine on.theappropriate tertiary amine. It is believed that addition takes placeat the less hinderednitrogen as indicated below. In the preferredpractice of this invention, the reactant tertiary amine dissolved in anunreactive solvent is exposed to a stream of gaseous chloramine. Theresultant hydrazinium chloride is isolated by conventional laboratorytechniques. Compounds containing anions other than chloride are preparedby metathesis starting with the chloride and a compound containing'theanion to be introduced.

In accordance with the present invention, I have made available a newclass of hydrazinium compounds having the general formula: I

RNHCOO I I N112 R R n In the above formula, R is a lower alkyl group andX is an anion bearing the charge 11.

When my compounds are used for pharmaceutical purposes, X must be apharmaceutically acceptable anion. The primary attributes of such ananion are nontoxicity and pharmaceutical compatibility. Otherwise, thechoice of the anion is of little consequence, since the primary activityof my novel compounds resides in the cation. The salts obtained byvariation of the anion may in some cases have special advantages due tosolubility, ease of crystallization, lack of objectionable taste and thelike, but these considerations are all subsidiary to the characteristicsof the cation which are independent of the character of the anion. Henceall variations of X are considered equivalent for the purpose of thepresent invention. Specific, but non-limiting, variants of X are asfollows: chloride, bromide, iodide, sulfate, bisulfate, acetate,salicylate, valerate, oleate, phenate, laurate, borate, benzoate,lactate, nitrate, diglycollate, phosphate, phenylethylbarbiturate,o-acetoxybenzoate, citrate, dialkylbarbiturate, sulfathiazole,theophyllinate, urate, maleate, fumarate, succinate, tartrate,diethylbarbiturate, penicillinate, camphorate, salicylamide,dephenylhydantoin, carbonate, cacodylate, aconitate, sulfamate,gentisate, malate and the like.

Patented Oct. 20, 1959 r, ce

One method of preparing the novel compounds of my invention is to reactchloramine with the tertiary amine corresponding to the desiredhydrazinium compound; the product is isolated and purified by standardlaboratory techniques. Since many of the amines are commerciallyavailable as their salts, the hydrochloride being the most common, ithas been found convenient to treat aqueous solutions of the amine saltswith base and extract the free amine with a solvent such as chloroform.After treatment of the extract with a conventional drying agent, thesolution is ready for chloramination. While chlora mine is mostadvantageously prepared as a gaseous chloramine-ammonia mixture obtainedfrom a generator constructed according to the teachings of Sisler etal., U. 8. Patent 2,710,248, other methods are equally adaptable for thepurpose of the present invention. For instance, chloramine can be madeby reacting chlorine with an excess of ammonia in carbon tetrachlorideor similar halogenated hydrocarbon solvents under controlled conditionsof mixing at-low temperatures. Such a process is fully described in U.S.Patent 2,678,258 to John F. Haller. Another effective procedure is thatof Coleman et al. fully described in Inorganic Syntheses, vol. I, 59(1939). Alternatively, the chloramine can be formed in the presence ofthe amine as described in the copending application Serial No. 605,230filed August 20, 1956, which teaches the reaction of chlorine and atertiary amine in the presence of excess ammonia. For simplicity, whenboth the amine and the product are soluble in the same inert solvent,e.g., chloroform, chloramine may be formed in situ by this method rightin the solution preformed chloramine is used and good absorption isrequired for efficient reaction, it has been found desirable to bubblechloramine through a long column of a solution comprising thetertiary'amine dissolved in relatively cheap inert solvent. By inertsolvent it is meant a solvent unreactive under the condition of thereaction. Solvents which servethis purpose include hydrocarbons, e.g.,heptane, cyclohexane, benzene, xylene and the like; ethers e.g., diethylether, diamyl ether, dioxane and anisole; amides, e.g.,dimethylformamide and dimethylacetamid'e; halohydrocarbons, e.g.,chloroform, carbon tetrachloride, trichloroethylene and chlorobenzene;nitroaromatics, e.g., nitrobenzene For special purposes, water and otherhydroxylic solvents such as ethyl alcohol and Cellosolve may be used.When the reaction is conducted in anhydrous solution, the product oftenprecipitates as the reaction progresses. In aqueous solution, however,it is usually necessary to concentrate or to evaporate to dryness inorder to isolate the product.

Another method of preparing the novel compounds of my invention is thereaction of hydroxylamine-o-sulfonic acid with tertiary amines. Thislatter method produced the hydraziniurn sulfate corresponding to thetertiary amine used. Preferably the appropriate tertiary amine andhydroxylamine-o-sulfonic acid are allowed to react or are heatedtogether in the presence of an alcoholic solvent but excess amine orother suitable solvents may be used. Even though the use of a solvent isnot required, superior results are obtained with a solvent because ofthe extremely exothermic reaction that quite often results. A frequentpurification step is the treatment of the reaction mixture with a basicsubstance such as sodium carbonate to remove acidic constituents fromthe product hydrazinium sulfate which is essentially neutral and stableto the action of base. Further purification is effected by standardlaboratory techniques.

It is obvious that not all of the novel hydrazinium compounds of myinvention are capable of being prepared directly as shown above. Inorder to provide the other useful salts of the present invention, it isnecessary to prepare the compounds containing anions other than chlorideor sulfate by metathesis. Many of the anions described supra can beobtained by mixing aqueous solutions of the hydrazinium chloride withappropriate re. agents. More often than not, the desired productprecipitates directly as the reaction progresses. This is the case wherethe new salt being formed is less soluble or insoluble in water. Othermetathetical approaches are available and the method selected depends onexperimental convenience, costs of reagents and the differences inphysical properties between the product and the starting material to beutilized in their separation. Reaction of a hydrazinium halide with asoluble silver salt, such as silver nitrate, results in theprecipitation of silver halide and the formation of the hydraziniumnitrate. In an analogous manner, treatment of the sulfate with a solublebarium salt results in the precipitation of barium sulfate andconversion to the anion of the barium salt. Quite often the appropriatereactants are heated together in the absence of a solvent and theproduct isolated by standard laboratory techniques. Another approachindependent of the formation of an insoluble solid, is to react thehalide with an excess of the desired anion as its acid; hydrogen halideis evolved as the new salt is formed. When it is necessary to prepare avery soluble salt, the reaction of the hydrazinium hydroxide withequivalent amounts of the appropriate acid may be utilized; thisapproach is also used for the preparation of very pure compounds.(Subjecting a hydrazinium halide to the action of moist silver oxidewill give the hydrazinium hydroxide.)

The scope and utility of my invention is furtherillustrated by thefollowing examples:

Example I Twenty-five grams of eserine sulfate was converted to the freebase by treatment with aqueous sodium bicarbonate and the eserineextracted with chloroform. The dried extract was reacted with .excesschloramine, filtered from the ammonium chloride formed and evaporated todryness. The residue was a hygroscopic light brown gum. Trituration ofthe gum with ether gave a brown powder which reverted to the gum onstanding in air. A portion of the powder was recrystallized from ethylalcohol-ethyl acetate to give a hygroscopic product melting 190-192 C.which darkened on exposure to air. 7

Example 11 Four grams of eserine sulfate was treated with aqueous 4sodium bicarbonate and two grams of the free base extracted withchloroform. The 400 ml. chloroform extract was dried, treated withexcess chloramine, filtered and evaporated to dryness. The two gramresidue was dissolved in a small amount of methyl alcohol and thesolution filtered into an excess of ethyl acetate. Filtration gave abouta gram of a light tan material melting 193 C.

Example III RNHOOO NH: R R

wherein R is a lower alkyl group and X is a pharmaceutically acceptableanion. I 2. Compounds according to claim 1 wherein R is methyl.

3. Compounds according to claim 2 wherein X is chloride.

References Cited in the file of this patent UNITED STATES PATENTSSchlitter et a1 July 17. 1956 OTHER REFERENCES Hoshino et al.: LiebigsAnn, 'vol. 520, pp. 11-12 (1935).

Polonovski: Comptes Rendus, vol. 179, pp. 334-336 (1924).

Chem. Abstracts, vol. 47, p. 2372b (1953), citing Laborit Therapie, vol.3, pp. 59-61 (1948).

Chem. Abstracts, vol. 49, p. 9710a (1955), citing Collier Biochem etBiophy. Acta, vol. 16, pp. 5838 (1955).

1. COMPOUNDS HAVING THE GENERAL FORMULA: 